Philadelphia chromosome positive acute lymphocytic leukemia (Ph+ALL) is an extremely refractory acute leukemia that cannot be cured by ordinary chemotherapies. In patients with Ph+ALL, fusion tyrosine kinases (BCR-ABL) with high activity are generated due to 9;22 chromosomal translocation.
Allogeneic hematopoietic stem cell transplantation has been the only way to cure Ph+ALL completely. However, the allogeneic hematopoietic stem cell transplantation has many problems to be addressed such as transplantation-related death, graft-versus-host disease and organ complication. Therefore, a new therapeutic strategy is needed to improve an outcome of treatment and maintain high quality of life (QOL) of the patients with Ph+ALL.
Recently, tyrosine kinase inhibitors (TKIs; imatinib, dasatinib, etc.), which are molecular targeted drugs for BCR-ABL, have been discovered and approved, resulting that prognosis has been improved by introducing them in actual treatment. However, its outcome has not reached to a satisfactory level yet.
Ikaros family zinc finger protein 1 (IKZF1) is an essential transcription factor for differentiation of all lymphoid cells. An IKZF1 gene has eight exons, exons 4 to 6 being DNA binding domains, and exon 8 encoding a dimerization domain (FIG. 1). Recently, it has been clearly found that presence or absence of an IKZF1 gene mutation is the most important factor for determining prognosis for treatment of ALL (Non-Patent Document 1). That is, prognosis in ALL with the IKZF1 gene mutation (one allele mutation) is related to extremely poor. Highly frequent gene mutations are defects of exons 4 to 7 (DNA binding defect) and defects of exons 1 to 8 (complete defect). The former acts as a dominant-negative (dominant inhibitory) isoform (Ik6) which inhibits formation of normal dimer having transcriptional activity. The latter shows haploinsufficiency. Frequency of the IKZF1 gene mutation in the patient with Ph+ALL is about 80% which is very high, and Ph+ALL is closely related to poor prognosis (Non-Patent Document 2). On the other hand, frequency of the IKZF1 gene mutation in Ph-negative ALL is a small percent. Therefore, proportion of ALL with the IKZF1 gene mutation is regulated by frequency of Ph+, and it has been reported that pediatric patients with low frequency of Ph+ are less than 15% and adult patients with high frequency of Ph+ is about 40%.
Derivatives with reduced toxicity of thalidomide such as lenalidomide and pomalidomide have various biological activities, which are referred to collectively as immunomodulators (IMiDs). These derivatives have been shown to be effective in treatment of multiple myeloma and certain myelodysplastic syndromes, and have already been clinically applied. Clinical trials of the thalidomide derivatives against malignant lymphoma, adult T cell leukemia lymphoma and the like are under way in the United States. However, effects of the thalidomide derivatives on ALL have not been fundamentally investigated so far. Therefore, no clinical trials for the thalidomide derivatives on ALL have been conducted.
Non-patent document 3 discloses that clinical trial to use lenalidomide and sunitinib against renal cell carcinoma was performed. Non-patent document 4 discloses that lenalidomide and dasatinib are used against multiple myeloma. Non-patent document 5 reports that treatment to use imatinib and lenalidomide was effective in multiple myeloma patients who developed chronic myelogenous leukemia at the same time as a rare case. Non-patent document 6 discloses that treatment of chronic myelogenous leukemia was performed by using imatinib and thalidomide. Non-patent document 7 discloses that treatment of chronic myeloid leukemia was performed by using imatinib and thalidomide. Non-patent documents 8 and 9 outline the significance of NFkB inhibitors for hematologic malignancies with high NFkB activity, such as multiple myeloma and chronic myelogenous leukemia.
Patent Document 1 discloses a method of treating a patient with Ph+ leukemia by using a BCR-ABL tyrosine kinase inhibitor and a drug for injection which selectively binds to various cytokine receptors (IL-3R, G-CSFR, GM-CSFR) expressed outside (on cell surface of) leukemic cells.